David B Kanne

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Spontaneous tumor-initiated T cell priming is dependent on IFN-β production by tumor-resident dendritic cells. On the basis of recent observations indicating that IFN-β expression was dependent upon activation of the host STING pathway, we hypothesized that direct engagement of STING through intratumoral (IT) administration of specific agonists would result(More)
Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and(More)
The nitroguanidine or nitromethylene moiety of the newest major class of insecticides, the neonicotinoids, is important for potency at insect nicotinic receptors and selectivity relative to mammalian receptors. Aldehyde oxidase (AOX) was recently identified as the imidacloprid nitroreductase of mammalian liver, producing both nitrosoguanidine and(More)
Imidacloprid (IMI), the prototypical neonicotinoid insecticide, is used worldwide for crop protection and flea control on pets. It is both oxidatively metabolized by cytochrome P450 enzymes and reduced at the nitroguanidine moiety by a previously unidentified cytosolic "neonicotinoid nitroreductase", the subject of this investigation. Two major metabolites(More)
Four neonicotinoid nitroguanidine insecticides (imidacloprid, thiamethoxam, clothianidin, and dinotefuran) acting as nicotinic agonists account for 10-15% of worldwide insecticide sales. General methods are needed for synthesis of their guanidine and aminoguanidine metabolites so they may be used as analytical standards and for evaluation of nicotinic(More)
Cytotoxic therapies prime adaptive immune responses to cancer by stimulating the release of tumor-associated antigens. However, the tumor microenvironment into which these antigens are released is typically immunosuppressed, blunting the ability to initiate immune responses. Recently, activation of the DNA sensor molecule STING by cyclic dinucleotides was(More)
A principal barrier to the development of effective vaccines is the availability of adjuvants and formulations that can elicit both effector and long-lived memory CD4 and CD8 T cells. Cellular immunity is the presumptive immune correlate of protection against intracellular pathogens: a group composed of bacteria, viruses and protozoans that is responsible(More)
The major neonicotinoid insecticide imidacloprid (IMI) is used worldwide for crop protection and pest control on pets. IMI is extensively metabolized, oxidatively by cytochromes P450 and via aerobic nitroreduction by the molybdo-flavoenzyme aldehyde oxidase (AOX). Rabbit liver AOX is capable of reducing IMI to both its nitrosoguanidine (IMI-NO) and(More)
The STING signaling pathway has emerged as a central TLR-independent mediator of host innate defense in response to sensing cytosolic nucleic acids, either through direct binding of CDNs secreted by intracellular bacteria, or through binding of a structurally distinct CDN produced by a host cell receptor, cyclic GMPAMP (cGAMP) synthase (cGAS), in response(More)
Stimulator of interferon genes (STING) signaling induces IFNβ production by intratumoral dendritic cells (DC), driving T-cell priming and recruitment into the tumor microenvironment (TME). We examined to what extent preexisting antigen-specific tolerance influenced the efficacy of in situ delivery of a potent STING-activating cyclic dinucleotide (CDN), ADU(More)